Composition and process

ABSTRACT

The present specification provides novel analogs of carbacyclin (CBA 2 ), 6a-carba-prostacyclin (6a-carba-PGI 2 ), which have pronounced prostacyclin-like pharmacological activity, e.g., as platelet antiaggregatory agents. Specifically the novel chemical analogs of CBA 2  are those substituted by fluoro (C-5), alkyl (C-9), interphenylene (C-5), and methano (C-6a,9). Further provided are benzindene analogs of CBA 2  and substituted forms thereof, i.e., 9-deoxy-2&#39;,9-methano (or 2&#39;,9-metheno)-3-oxa-4,5,6-trinor-3,7-(1&#39;,3&#39;-interphenylene)-PGF 1  compounds. Also provided are a variety of novel chemical intermediates, e.g., substituted bicyclo[3.3.0]octane intermediates, and chemical process utilizing such intermediates which are useful in the preparation of the novel CBA 2  analogs.

This application is a continuation-in-part of Ser. No. 125,608, filedFeb. 28, 1980, and now U.S. Pat. No. 4,338,457.

DESCRIPTION BACKGROUND OF THE INVENTION

The present invention relates to novel compositions of matter and novelprocesses for preparing these compositions of matter. Moreover, thereare provided novel methods by which certain of these novel compositionsof matter are employed for pharmacologically useful purposes. Furtherthere are provided novel chemical intermediates for preparing thesecompositions of matter.

The present invention is specifically concerned with novel analogs ofprostacyclin or PGI₂. Specifically, the present invention is concernedwith analogs of carbacyclin modified at the C-5 or C-9 position, e.g.,C-5 inter-phenylene analogs of carbacyclin, 5-fluoro analogs ofcarbacyclin, 9β-alkyl analogs of carbacyclin, C-6a,9 tricyclic(cyclopropyl) analogs of carbacyclin, and combinations thereof as wellas novel benzindene analogs thereof.

Prostacyclin is an endogenously produced compound in mammalian species,being structurally and biosynthetically related to the prostaglandins(PG's). In particular, prostacyclin exhibits the structure and carbonatom numbering of formula I when the C-5,6 positions are unsaturated.For convenience, prostacyclin is often referred to simply as "PGI₂ ".Carbacyclin, 6a-carba-PGI₂, exhibits the structure and carbon atomnumbering indicated in formula II when the C-5,6 positions areunsaturated. Likewise, for convenience, carbacyclin is referred tosimply as "CBA₂ ".

A stable partially saturated derivative of PGI₂ is PGI₁ or5,6-dihydro-PGI₂ when the C-5,6 positions are saturated, depicted withcarbon atom numbering in formula II when the C-5,6 positions aresaturated. The corresponding 5,6-dihydro-CBA₂ is CBA₁, depicted informula II.

As is apparent from inspection of formulas I and II, prostacyclin andcarbacyclin may be trivially named as derivatives of PGF-type compounds,e.g., PGF₂ α of formula III. Accordingly, prostacyclin is triviallynamed 9-deoxy-6,9α-epoxy-(5Z)-5,6-didehydro-PGF₁ and carbacyclin isnamed 9-deoxy-6,9α-methano-(5E)-5,6-didehydro-PGF₁. For description ofprostacyclin and its structural identification, see Johnson, et. al.,Prostaglandins 12:915 (1976).

For convenience, the novel prostacyclin or carbacyclin analogs will bereferred to by the trivial, art-recognized system of nomenclaturedescribed by N. A. Nelson, J. Med. Chem. 17:911 (1974) forprostaglandins. Accordingly, all of the novel prostacyclin derivativesherein will be named as 9-deoxy-PGF₁ -type compounds, PGI₂ derivatives,or preferably as CBA₁ or CBA₂ derivatives.

In the formulas herein, broken line attachments to a ring indicatesubstituents in the "alpha" (α) configuration, i.e., below the plane ofsaid ring. Heavy solid line attachments to a ring indicate substituentsin the "beta" (β) configuration, i.e., above the plane of said ring. Theuse of wavy lines (˜) herein will represent attachment of substituentsin the alpha or beta configuration or attached in a mixture of alpha andbeta configurations. Alternatively wavy lines will represent either an Eor Z geometric isomeric configuration or the mixture thereof.

A side chain hydroxy at C-15 in the formulas herein is in the S or Rconfiguration as determined by the Cahn-Ingold-Prelog sequence rules, J.Chem. Ed. 41:16 (1964). See also Nature 212:38 (1966) for discussion ofthe stereochemistry of the prostaglandins which discussion applies tothe novel prostacyclin or carbacyclin analogs herein. Molecules ofprostacyclin and carbacyclin each have several centers of asymmetry andtherefore can exist in optically inactive form or in either of twoenantiomeric (optically active) forms, i.e., the dextrorotatory andlaveorotatory forms. As drawn, the formula for PGI₂ corresponds to thatendogenously produced in the mammalian species. In particular, refer tothe stereochemical configuration at C-8 (α), C-9 (α), C-11 (α) and C-12(β) of endogenously produced prostacyclin. The mirror image of the aboveformula for prostacyclin represents the other enantiomer. The racemicform of prostacyclin contains equal numbers of both enantiomericmolecules.

For convenience, reference to prostacyclin and carbacyclin will refer tothe optically active form thereof. Thus, with reference to prostacyclin,reference is made to the form thereof with the same absoluteconfiguration as that obtained from the mammalian species.

The term "prostacyclin-type" product, as used herein, refers to anycyclopentane derivative herein which is useful for at least one of thesame pharmacological purposes for which prostacyclin is employed. Aformula as drawn herein which depicts a prostacyclin-type product or anintermediate useful in the preparation thereof, represents thatparticular stereoisomer of the prostacyclin-type product which is of thesame relative stereochemical configuration as prostacyclin obtained frommammalian tissues or the particular stereoisomer of the intermediatewhich is useful in preparing the above stereoisomer of the prostacyclintype product.

The term "prostacyclin analog" or "carbacyclin analog" represents thatstereoisomer of a prostacyclin-type product which is of the samerelative stereochemical configuration as prostacyclin obtained frommammalian tissues or a mixture comprising stereoisomer and theenantiomers thereof. In particular, where a formula is used to depict aprostacyclin type product herein, the term "prostacyclin analog" or"carbacyclin analog" refers to the compound of that formula or a mixturecomprising that compound and the enantiomer thereof.

PRIOR ART

Carbacyclin and closely related compounds are known in the art. SeeJapanese Kokia 63,059 and 63,060, also abstracted respectively asDerwent Farmdoc CPI Numbers 48154B/26 and 48155B/26. See also Britishpublished specifications 2,012,265 and German Offenlungsschrift2,900,352, abstracted as Derwent Farmdoc CPI Number 54825B/30. See alsoBritish published applications Nos. 2,017,699, 2,014,143 and 2,013,661.

The synthesis of carbacyclin and related compounds is also reported inthe chemical literature, as follows: Morton, D. R., et al., J. OrganicChemistry, 44:2880 (1979); Shibasaki, M., et al. Tetrahedron Letters,433-436 (1979); Kojima, K., et al., Tetrahedron Letters, 3743-3746(1978); Nicolaou, K. C., et al., J. Chem. Soc., Chemical Communications,1067-1068 (1978); Sugie, A., et al., Tetrahedron Letters 2607-2610(1979); Shibasaki, M., Chemistry Letters, 1299-1300 (1979), and Hayashi,M., Chem. Lett. 1437-40 (1979); and Li, Tsung-tee, "A Facile Synthesisof 9(O)-Methano-prostacyclin", Abstract No. 378, (Organic Chemistry),and P. A. Aristoff, "Synthesis of 6a-Carbaprostacyclin I₂ ", AbstractNo. 236 (Organic Chemistry) both at Abstract of Papers (Part II) SecondCongress of the North American Continent, San Francisco, California (LasVegas, Nevada), USA, 24-29 August 1980.

7-Oxo and 7-hydroxy-CBA₂ compounds are apparently disclosed in U.S. Pat.No. 4,192,891. 19-Hydroxy-CBA₂ compounds are disclosed in U.S. Ser. No.54,811, filed July 5, 1979. CBA₂ aromatic esters are disclosed in U.S.Pat. No. 4,180,657. 11-Deoxy-Δ¹⁰ - or Δ¹¹ -CBA₂ compounds are describedin Japanese Kokai 77/24,865, published Feb. 24, 1979.

SUMMARY OF THE INVENTION

The present specification particularly provides:

(a) a carbacyclin intermediate of formula IV, V, VI, VII, VIII, or IX;and

(b) a carbacyclin analog of formula X or XI; wherein g is 0, 1, 2, or 3;

wherein n is one or 2;

wherein L₁ is α-R₃ :β-R₄, α-R₄ :β-R₃, or a mixture of α-R₃ :β-R₄ andα-R₄ :β-R₃, wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being thesame or different, with the proviso that one of R₃ and R₄ is fluoro onlywhen the other is hydrogen or fluoro;

wherein M₁ is α-OH:β-R₅ or α-R₅ :β-OH, wherein R₅ is hydrogen or methyl;

wherein M₆ is α-OR₁₀ :β-R₅ or α-R₅ :β-OR₁₀, wherein R₅ is hydrogen ormethyl and R₁₀ is an acid hydrolyzable protective group;

wherein R₇ is

(1) --C_(m) H_(2m) --CH₃, wherein m is an integer from one to 5,inclusive,

(2) phenoxy optionally substituted by one, two or three chloro, fluoro,trifluoromethyl, (C₁ -C₃)alkyl, or (C₁ -C₃)alkoxy, with the proviso thatnot more than two substituents are other than alkyl, with the provisothat R₇ is phenoxy or substituted phenoxy, only when R₃ and R₄ arehydrogen or methyl, being the same or different,

(3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substitutedon the aromatic ring by one, two or three chloro, fluoro,trifluoromethyl, (C₁ -C₃)alkyl, or (C₁ -C₃)alkoxy, with the proviso thatnot more than two substituents are other than alkyl,

(4) cis--CH═CH--CH₂ --CH₃,

(5) --(CH₂)₂ --CH(OH)--CH₃, or

(6) --(CH₂)₃ --CH═C(CH₃)₂ ;

wherein --C(L₁)--R₇ taken together is

(1) (C₄ -C₇)cycloalkyl optionally substituted by one to 3 (C₁ -C₅)alkyl;

(2) 2-(2-furyl)ethyl,

(3) 2-(3-thienyl)ethoxy, or

(4) 3-thienyloxymethyl;

wherein R₈ is hydroxy, hydroxymethyl., or hydrogen;

wherein R₁₅ is hydrogen or fluoro;

wherein R₁₆ is hydrogen or R₁₆ and R₁₇ taken together are --CH₂ -- orR₁₆ and R₄₇ taken together form a second valence bond between C-6a andC-9 or are --CH₂ --;

wherein R₁₇ is as defined above or is

(1) hydrogen, or

(2) (C₁ -C₄)alkyl;

wherein R₁₈ is hydrogen, hydroxy, hydroxymethyl, --OR₁₀ or --CH₂ OR₁₀,wherein R₁₀ is an acid-hydrolyzable protective group; wherein

(1) R₂₀, R₂₁, R₂₂, R₂₃, and R₂₄ are all hydrogen with R₂₂ being eitherα-hydrogen or β-hydrogen,

(2) R₂₀ is hydrogen, R₂₁ and R₂₂ taken together form a second valencebond between C-9 and C-6a, and R₂₃ and R₂₄ taken together form a secondvalence bond between C-8 and C-9 or are both hydrogen, or

(3) R₂₂, R₂₃, and R₂₄ are all hydrogen, with R₂₂ being either α-hydrogenor β-hydrogen, and

(a) R₂₀ and R₂₁ taken together are oxo, or

(b) R₂₀ is hydrogen and R₂₁ is hydroxy, being α-hydroxy or β-hydroxy;

wherein R₂₇ is the same as R₇ except that --(CH₂)₂ --CH(OH)--CH₃ is--(CH₂)--CH(OR₁₁)--CH₃ ;

wherein R₃₂ is hydrogen or R₃₁, wherein R₃₁ is a hydroxyl hydrogenreplacing group;

wherein R₃₃ is --CHO or --CH₂ OR₃₂, wherein R₃₂ is as defined above;

wherein R₄₇ is as defined above or is

(1) (C₁ -C₄)alkyl, or

(2) --CH₂ OH;

wherein X₁ is

(1) --COOR₁, wherein R₁ is

(a) hydrogen,

(b) (C₁ -C₁₂)alkyl,

(c) (C₃ -C₁₀)cycloalkyl,

(d) (C₇ -C₁₂)aralkyl,

(e) phenyl, optionally substituted with one, 2 or 3 chloro or (C₁-C₃)alkyl,

(f) phenyl substituted in the para position by

(i) --NH--CO--R₂₅,

(ii) --CO--R₂₆,

(iii) --O--CO--R₅₄, or

(iv) --CH═N--NH--CO--NH₂ wherein R₂₅ is methyl, phenyl, acetamidophenyl,benzamidophenyl, or --NH₂ ; R₂₆ is methyl, phenyl, --NH₂, or methoxy;and R₅₄ is phenyl or acetamidophenyl; inclusive, or

(g) a pharmacologically acceptable cation;

(2) --CH₂ OH,

(3) --COL₄, wherein L₄ is

(a) amino of the formula --NR₅₁ R₅₂, wherein R₅₁ and R₅₂ are

(i) hydrogen,

(ii) (C₁ -C₁₂)alkyl,

(iii) (C₃ -C₁₀)cycloalkyl,

(iv) (C₇ -C₁₂)aralkyl,

(v) phenyl, optionally substituted with one, 2 or 3 chloro, (C₁-C₃)alkyl, hydroxy, carboxy, (C₂ -C₅)alkoxycarbonyl, or nitro,

(vi) (C₂ -C₅)carboxyalkyl,

(vii) (C₂ -C₅)carbamoylalkyl,

(viii) (C₂ -C₅)cyanoalkyl,

(ix) (C₃ -C₆)acetylalkyl,

(x) (C₇ -C₁₁)benzoalkyl, optionally substituted by one, 2 or 3 chloro,(C₁ -C₃)alkyl, hydroxy, (C₁ -C₃)alkoxy, carboxy, (C₂ -C₅)alkoxycarbonyl,or nitro,

(xi) pyridyl, optionally substituted by one, 2 or 3 chloro, (C₁-C₃)alkyl, or (C₁ -C₃)alkoxy,

(xii) (C₆ -C₉)pyridylalkyl optionally substituted by one, 2 or 3 chloro,(C₁ -C₃)alkyl, hydroxy, or (C₁ -C₃)alkyl,

(xiii) (C₁ -C₄)hydroxyalkyl,

(xiv) (C₁ -C₄)dihydroxyalkyl,

(xv) (C₁ -C₄)trihydroxyalkyl, with the further proviso that not morethan one of R₅₁ and R₅₂ is other than hydrogen or alkyl,

(b) cycloamino selected from the group consisting of pyrolidino,piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or3,4-didehydropiperidinyl optionally substituted by one or 2 (C₁-C₁₂)alkyl of one to 12 carbon atoms, inclusive,

(c) carbonylamino of the formula --NR₅₃ COR₅₁, wherein R₂₃ is hydrogenor (C₁ -C₄)alkyl and R₅₁ is other than hydrogen, but otherwise asdefined above,

(d) sulfonylamino of the formula --NR₅₃ SO₂ R₅₁, wherein R₂₁ and R₂₃ areas defined in (c),

(4) --CH₂ NL₂ L₃, wherein L₂ and L₃ are hydrogen or (C₁ -C₄)alkyl, beingthe same or different, or the pharmacologically acceptable acid additionsalts thereof when X₁ is --CH₂ NL₂ L₃,

wherein Y₁ is trans--CH═CH--, cis--CH═CH--, --CH₂ CH₂ --, or--C.tbd.C--;

wherein Z₁ is

(1) --CH₂ --(CH₂)_(f) --C(R₂)₂, wherein R₂ is hydrogen or fluoro and fis zero, one, 2, or 3,

(2) trans--CH₂ --CH═CH--,

(3) --(Ph)--(CH₂)_(g) --, wherein (Ph) is 1,2-, 1,3-, or 1,4-phenyleneand g is zero, one, 2, or 3;

wherein Z₄ is --CH₂ -- or --(CH₂)_(f) --CF₂, wherein f is as definedabove;

with the overall proviso that

(1) R₁₅, R₁₆, and R₁₇ are all hydrogen only when Z₁ is --(Ph)--(CH₂)_(g)--, and

(2) Z₁ is --(Ph)--(CH₂)_(g) -- only when R₁₅ is hydrogen.

The detailed description, preparation, and use of the present inventionis incorporated herein by reference from U.S. Pat. No. 4,306,075beginning at column 5, line 36 through column 95, line 43.

I claim:
 1. The carbacyclin intermediate of formula IV or V: ##STR1##wherein n is one or 2; wherein L₁ is α-R₃ :β-R₄, α-R₄ :β-R₃, or amixture of α-R₃ :β-R₄ and α-R₄ :β-R₃, and wherein R₃ and R₄ arehydrogen, methyl, or fluoro, being the same or different, with theproviso that one of R₃ and R₄ is fluoro only when the other is hydrogenor fluoro;wherein M₆ is α-OR₁₀ :β-R₅ or α-R₅ :β-OR₁₀, wherein R₅ ishydrogen or methyl and R₁₀ is an acid hydrolyzable protective group;wherein R₂₇ is(1) --C_(m) H_(2m) --CH₃, wherein m is an integer from oneto 5, inclusive, (2) phenoxy optionally substituted by one, two or threechloro, fluoro, trifluoromethyl, (C₁ -C₃)alkyl, or (C₁ -C₃)alkoxy, withthe proviso that not more than two substituents are other than alkyl,with the proviso that R₂₇ is phenoxy or substituted phenoxy, only whenR₃ and R₄ are hydrogen or methyl, being the same or different, (3)phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted onthe aromatic ring by one, two or three chloro, fluoro, trifluoromethyl,(C₁ -C₃)alkyl, or (C₁ -C₃)alkoxy, with the proviso that not more thantwo substituents are other than alkyl, (4) cis--CH═CH--CH₂ --CH₃, (5)--(CH₂)₂ --CH(OR₁₀)--CH₃, wherein R₁₀ is as defined above, or (6)--(CH₂)₃ --CH═C(CH₃)₂ ; wherein --C(L₁)--R₂₇ taken together is(1) (C₄-C₇)cycloalkyl optionally substituted by one to 3 (C₁ -C₅)alkyl; (2)2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl;wherein R₁₈ is hydrogen, hydroxy, hydroxymethyl, --OR₁₀ or --CH₂ OR₁₀,wherein R₁₀ is an acid-hydrolyzable protective group; wherein R₃₂ ishydrogen or R₃₁, wherein R₃₁ is a hydroxyl hydrogen protective group;and wherein Y₁ is trans--CH═CH--, cis--CH═CH--, --CH₂ CH₂ --, or--C.tbd.C--.